Naphthyridine derivatives

Abstract

2-Oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by bearing a specific substituent, —X—R 6 , at the 3-position and a cyclic substituent, R 5 , at the 4-position; or salts thereof. The derivatives and the salts are useful as drugs, particularly preventive or therapeutic agents for respiratory diseases related to PDE IV.

What is claimed is:  
     
       1. A naphthynidine derivative represented by the following formula (I′) or a pharmaceutically acceptable salt thereof                    
       (wherein each symbol has the following meaning; 
       R 1 : —R 0 , -a lower alkylene-cycloalkyl or -a cycloalkyl  
       R 0 : -a lower alkyl,  
       R 2 , R 3 , and R 4 : —H, —R 0 , -a halogen, -a lower alkylene-OH, -a lower alkylene-SH, -a lower-alkylene-O—R 0 , -a lower alkylene-S—R 0 , -a lower alkylene-O—CO—R 0 , -a lower alkylene-S—CO—R 0 , —OH, —O—R 0 , —S—R 0 , —SO—R 0 , —SO 2 —R 0 , —NH 2 , —NHR 0 , —NR 0   2 , -a cycloalkyl, —CO—R 0 , or —CH═N—OR 9 , which may be the same or different from one another,  
       R 9 : —H, —R 0  or -a lower alkylene-aryl,  
       R 5 : a cycloalkyl which may be substituted with a group selected from R 10 , a cycloalkenyl which may be substituted with a group selected from R 10 , or phenyl which may be substituted with a group selected from R 10 ,  
       R 6 : —OH, —OR 7 , —COOH, —COOR 7 , —CONH 2 , —CONHR 7 , —CON(R 7 ) 2 , —O—COR 7 , —O—COOR 7 , —CHO, —COR 7 , —NH 2 , —NHR 7 , —N(R 7 ) 2 , —NHCOR 7 , —N(R 7 )COR 7 , —NHSO 2 R 7 , —N(R 7 )SO 2 R 7 , —CN, —NHCOOR 7 , —N(R 7 )COOR 7 , —C(NH)NH 2 , —NHC(NH)NH 2  or —N(R 7 )C(NH)NH 2 , or a group represented by the formula —Y—R 8 ,  
       R 7 : a lower alkyl which may be substituted with a group selected from the group consisting of —OH, -phenyl, -a halogen, —OR 0 , —CO 2 H, —CO 2 R 0 , —NH 2 , —NHR 0 , —NR 0   2 , —NO 2 , —CN, and —COR 0 ,  
       R 8 : a cycloalkyl which may be substituted with a group selected from R 10 , an aryl which may be substituted with a group selected from R 10 , or a heterocyclic group which may be substituted with a group selected from R 10 ,  
       R 10 : —OH, -phenyl, -a halogen, —OR 0 , —CO 2 H, —CO 2 R 0 , —NH 2 , —NHR 0 , —NRO 2 , —NO 2 , —CN or —COR 0 , or a group described in R 7 .  
       Y: a bond, —O—, —COO—, —CONH—, —CON(R 7 )—, —O—CO—, —O—COO—, —CO—, —NH—, —N(R 7 )—, —NHCO—, —N(R 7 )CO—, —NHCOO—, —N(R 7 )COO—, —NHSO 2 —, or —N(R 7 )SO 2 —, and  
       X: a bond, a lower alkylene, or a lower alkenylene,  
       provided that, when X is a bond, then R 6  is —Y—R 8  and Y is a bond). 
     
     
       2. The naphthyridine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein X is a bond or a lower alkylene and R 6 is —OH, —COOH, —COOR 7 , —O—COR 7 , —NH 2 , —NHR 7 , —N(R 7 ) 2 , —C(NH)NH 2 , —NHC(NH)NH 2  or —N(R 7 )C(NH)NH 2 , or a group represented by the formula —Y—R 8 . 
     
     
       3. The naphthyridine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 5  is cyclohexyl or phenyl substituted with a halogen. 
     
     
       4. The naphthyridine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , which is selected from the group consisting of 3-(2-amidinoethyl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one, 4-(3-chlorophenyl)-1-ethyl-3-(2-guanidinoethyl)-7-methyl-1,8-naphthyridin-2(1H)-one, 4-cyclohexyl-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthyridin-2(1H)-one, 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(1H-tetrazol-5-yl)propyl]-1,8-naphthyridin-2(1H)-one, 4-(3-bromophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthyridin-2(1H)-one, 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, 3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid, 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]benzoic acid, 3-[4-(3-chlorophenyl)-1-ethyl-7-(hydroxyiminomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, 3-[7-chloro-4-(3-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, 3-[1-ethyl-7-methyl-4-(3-methylphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one and 1-{2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]ethyl}piperidine-4-carboxylic acid. 
     
     
       5. A pharmaceutical composition which comprises the naphthyridine derivative of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       6. A pharmaceutical composition, which comprises a naphthyridine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof as a type IV phosphodiesterase inhibitor, and a pharmaceutically acceptable carrier                    
       (wherein each symbol has the following meaning; 
       R 1 : —R 0 , -a lower alkylene-cycloalkyl or -a cycloalkyl  
       R 0 : -a lower alkyl,  
       R 2 , R 3 , and R 4 : —H, —R 0 , -a halogen, -a lower alkylene-OH, -a lower alkylene-SH, -a lower alkylene-O—R 0 , -a lower alkylene-S—R 0 , -a lower alkylene-O—CO—R 0 , -a lower alkylene-S—CO—R 0 , —OH, —O—R 0 , —S—R 0 , —SO—R 0 , —SO 2 —R 0 , —NH 2 , —NHR 0 , —NR 0   2 , -a cycloalkyl, —CO—R 0 , or —CH═N—OR 9 , which may be the same or different from one another,  
       R 9 : —H, —R 0  or -a lower alkylene-aryl,  
       R 5 : a cycloalkyl which may be substituted with a group selected from R 10 , a cycloalkenyl which may be substituted with a group selected from R 10 , or phenyl which may be substituted with a group selected from R 10 ,  
       R 6 : —OH, —OR 7 , —COOH, —COOR 7 —CONH 2 , —CONHR 7 , —CON(R 7 ) 2 , —O—COR 7 , —O—COOR 7 , —CHO, —COR 7 , —NH 2 , —NHR 7 , —N(R 7 ) 2 , —NHCOR 7 , —N(R 7 )COR 7 , —NHSO 2 R 7 , —N(R 7 )SO 2 R 7 , —CN, —NHCOOR 7 , —N(R 7 )COOR 7 , —C(NH)NH 2 , —NHC(NH)NH 2  or —N(R 7 )C(NH)NH 2 , or a group represented by the formula —Y—R 8 ,  
       R 7 : a lower alkyl which may be substituted with a group selected from the group consisting of —OH, -phenyl, -a halogen, —OR 0 , —CO 2 H, —CO 2 R 0 , —NH 2 , —NHR 0 , —NR 0   2 , —NO 2 , —CN, and —COR 0 ,  
       R 8 : a cycloalkyl which may be substituted with a group selected from R 10 , an aryl which may be substituted with a group selected from R 10 , or a heterocyclic group which may be substituted with a group selected from R 10 ,  
       R 10 : —OH, -phenyl, -a halogen, —OR 0 , —CO 2 H, —CO 2 R 0 , —NH 2 , —NHR 0 , —NR 0   2 , —NO 2 , —CN or —COR 0 , or a group described in R 7 .  
       Y: a bond, —O—, —COO—, —CONH—, —CON(R 7 )—, —O—CO—, —O—COO—, —CO—, —NH—, —N(R 7 )—, —NHCO—, —N(R 7 )CO—, —NHCOO—, —N(R 7 )COO—, —NHSO 2 —, or —N(R 7 ) 0 2 —, and  
       X: a bond, a lower alkylene, or a lower alkenylene).  
     
     
       7. The pharmaceutical composition according to  claim 6 , which is an agent for preventing or treating respiratory diseases. 
     
     
       8. The pharmaceutical composition according to  claim 7 , which is an agent for preventing or treating bronchial asthma.